Substituted-1,2,3,4-tetrahydroisoquinoline derivatives are useful in the synthesis of a variety of pharmaceutical agents. Synthesis of these intermediates however, has typically been difficult for a number of reasons.
For example, 6-methoxy-1,2,3,4-tetrahydroisoquinoline, although commercially available, is at present very expensive (>$400/g) and available only in milligram quantity as listed by few chemical sources. Further, although several syntheses of this compound have been reported in the literature, none are convenient to carry out on large-scale. Among the published approaches, the most direct method of tetrahydroisoquinoline formation appears to be Pictet-Spengler type condensation of 2-(3′-methoxyphenyl)ethylamine with formaldehyde (a) Whaley, W. M.; Govindachari, T. R. Organic Reactions, 1951, 6, 151. b) Ivanov, I., Venkov, A. Heterocycles, 2001, 55, 1569. c) Bates, H. A. J. Org. Chem., 1983, 48, 4931-4935. d) Bates, H. A.; Bagheri, K.; Vertino, P. M. J. Org. Chem., 1986, 51 3061-3063). Several research groups have used this approach to obtain the target compound in small quantity. However, the product resulting from the direct condensation of 2-(3′-methoxyphenyl)ethylamine with formaldehyde is an oil, making the isolation and purification difficult for large-scale synthesis purposes (a) Bojaeski, A. J.; Mokrosz, M. J.; Minol, S. C.; Koziol, A.; Wesolowska, A.; Tatarczynska, E.; Klodzinska, A.; Chojnacka-Wojcik, E. Bioorg, Med. Chem., 2002, 10, 87-95. b) Euerby, M. R.; Waigh, R. D. J. Chem. Res., Synopses, 1987, 2, 36-7).
Bucks, J. S. in J. Am. Chem. Soc., 1934, Vol 56., pp 1769-1771 has reported the direct isolation of a HCl salt of 6-methoxy-1,2,3,4-tetrahydroisoquinoline requiring time-consuming evaporation of aqueous HCl solution to dryness.
In addition to the direct condensation of 2-(3′-methoxyphenyl)ethylamine with formaldehyde, some approaches described in the literature required a protection of amine functionality prior to the acid-catalyzed condensation, followed by another deprotection step after the condensation. (Bojaeski, A. J.; Mokrosz, M. J.; Minol, S. C.; Koziol, A.; Wesolowska, A.; Tatarczynska, E.; Klodzinska, A.; Chojnacka-Wojcik, E. Bioorg, Med. Chem., 2002, 10, 87-95; Stokker, G. E. Tetrahedral Lett., 1996, 37, 5453-5456).
An alternative approach reported by Sall, D. J.; Grunewald, G. L., in J. Med. Chem. 1987, 30, 2208-2216 used a Fridal-Crafts type cyclization of methyl 2-(3′-methoxyphenyl)ethyl carbamate with polyphosphoric acid (PPA) to yield a mixture of 6-methoxy- and 8-methoxy-3,4-dihydroisoquinolin-one in a ratio of 2:1, respectively. After separation of the regioisomers by chromatography, lithium aluminum hydride reduction yielded the corresponding 6-methoxy- and 8-methoxy-1,2,3,4-tetrahydroisoquinoline. Although the procedure was recently utilized by Mewshaw and coworkers for their medicinal chemistry research (Meagher, K. L.; Mewshaw, R. E.; Evrard, D. A.; Zhou, P.; Smith, D. L.; Scerni, R.; Spangler, T.; Abulhawa, S.; Shi, X.; Schechter, L. E.; Andree, T. H. Bioorg. Med. Chem. Lett. 2001, 11, 1885-1888), the poor regioselectivity of cyclization and harsh reaction conditions prevented its application in large-scale synthesis.
Thus there remains a need for a method for the synthesis of substituted-1,2,3,4-tetrahydroisoquinoline derivatives, and more particularly, 6-methoxy-1,2,3,4-tetrahydroisoquinoline, which is suitable for large scale production.